Chapter Eight - Orexin/Hypocretin System: Role in Food and Drug Overconsumption
Introduction
In 1998, the neuropeptide orexin/hypocretin (OX) was identified independently by two different laboratories, both of which suggested that it played a major role in food intake and energy homeostasis (de Lecea et al., 1998, Sakurai et al., 1998). Although the cell bodies that transcribe this neuropeptide were shown to be largely restricted to the hypothalamus that regulates food intake, these neurons were also found to send extensive projections throughout the brain, most notably to the limbic system (Peyron et al., 1998, Trivedi et al., 1998). Numerous studies over the past 20 years have demonstrated that hypothalamic OX neurons and their projections have broader functions beyond homeostatic food intake, controlling a range of other adaptive behaviors such as sleep–wake regulation, mating, and maternal behavior. Of particular interest is the additional evidence that OX promotes dysregulated, nonhomeostatic intake, such as occurs with abused, rewarding substances. It stimulates excessive intake of palatable sweet and fatty foods, alcohol, nicotine, and cocaine among other substances, and in many cases, it is in turn stimulated by their intake as part of a positive feedback loop. This is the focus of the present review.
Section snippets
Anatomy of Orexin/Hypocretin-Expressing Neurons
The first description of OX came from de Lecea et al. (1998), who identified a gene which they termed hypocretin, given its nearly exclusive expression in the hypothalamus and its similar amino acid sequence to the gut hormone secretin. These authors noted that this precursor gene actually encodes two peptides, which they termed hypocretin 1 and hypocretin 2 (de Lecea et al., 1998). Soon thereafter, Sakurai et al. (1998) identified the same 130 amino acid neuropeptide gene, which they termed
Role of Orexin/Hypocretin in Homeostatic Feeding and Other Adaptive Behaviors
While OX was originally noted for its role in food intake and energy homeostasis, it soon became apparent that this neuropeptide participates in a host of other behaviors, many of which serve to promote survival. These include not only homeostatic food intake but also sleep–wake regulation, mating behavior, and maternal behavior.
Role of Orexin/Hypocretin in Nonhomeostatic Intake
Whereas adaptive behaviors are generally performed in a homeostatic manner that involves negative feedback, the intake of rewarding substances of abuse is often nonhomeostatic, involving a positive feedback loop that promotes overconsumption. While the mechanisms behind these adaptive and overconsumption behaviors may seem distinct, the behaviors are known to share in common their functioning through dopamine in the nucleus accumbens shell. Levels and release of accumbal dopamine are increased
Conclusions
While OX was originally identified for its role in food intake and energy homeostasis, it has since become clear that OX participates in a range of behaviors, which are both homeostatically and nonhomeostatically regulated. Many of the behaviors promoted by OX can be classified as adaptive, including food intake, sleep–wake regulation, mating, and maternal behavior. These behaviors are largely controlled by the release of OX in the hypothalamus, with food intake involving the same regions of
Acknowledgments
This research was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under Award Numbers R00AA021782 (J.R.B.) and R01AA24798 (S.F.L.). We thank Dr. Rodrigo A. España (Drexel University College of Medicine) for his invaluable assistance in interpreting portions of the cocaine literature.
References (202)
- et al.
Neural substrates of awakening probed with optogenetic control of hypocretin neurons
Nature
(2007) - et al.
Reduced food anticipatory activity in genetically orexin (hypocretin) neuron-ablated mice
The European Journal of Neuroscience
(2004) - et al.
Binge-like consumption of caloric and non-caloric palatable substances in ad libitum-fed C57BL/6J mice: Pharmacological and molecular evidence of orexin involvement
Behavioural Brain Research
(2014) - et al.
Orexin-1 and orexin-2 receptor antagonists reduce ethanol self-administration in high-drinking rodent models
Frontiers in Neuroscience
(2014) - et al.
Orexin gene expression and regulation by photoperiod in the sheep hypothalamus
Regulatory Peptides
(2002) - et al.
Chemical coding of GABA(B) receptor-immunoreactive neurones in hypothalamic regions regulating body weight
Journal of Neuroendocrinology
(2003) - et al.
Orexin receptor-1 (OX-R1) immunoreactivity in chemically identified neurons of the hypothalamus: Focus on orexin targets involved in control of food and water intake
The European Journal of Neuroscience
(2002) - et al.
Cellular localization of GABA receptor alpha subunit immunoreactivity in the rat hypothalamus: Relationship with neurones containing orexigenic or anorexigenic peptides
Journal of Neuroendocrinology
(2004) - et al.
Effects of intranasal hypocretin-1 (orexin A) on sleep in narcolepsy with cataplexy
Sleep Medicine
(2011) - et al.
Smoking, alcohol, drug use, abuse and dependence in narcolepsy and idiopathic hypersomnia: A case-control study
Sleep
(2016)